Xerostomia can be defined as the subjective sensation of dryness of the mouth. This is usually the result of a decrease in the volume of saliva secreted but may also be due to a change in composition of saliva. Salivary gland hypofunction is defined as demonstrable reduction in either whole or individual gland flow rates. Salivary gland dysfunction has been used as an umbrella term to describe patients with xerostomia and/or salivary gland hypofunction. The prevalence of xerostomia in the general population is between 22-26% and is more common in patients with chronic illness, for example in the palliative care population the prevalence is between 82-83%. The most common cause for salivary gland hypofunction is drug treatment; another cause is Sjogrens syndrome.
Xerostomia is an important condition in cancer patients. In head and neck cancer patients, xerostomia arises from collateral radiation damage to the salivary glands. As many as 95% of head and neck cancer patients suffer significant xerostomia, although head and neck cancer represents less than 5% of all cancers. Xerostomia is also a problem in the broader cancer population. These patients suffer xerostomia principally as a result of the medications they receive. These may include cytotoxic chemotherapy agents such as 5-fluorouracil, paclitaxel, platinum compounds and busulphan, antineoplastic hormonal agents including anastrozole and bicalutamide; and concomitant medications not specifically given for cancer but common especially in advanced cancer patients, such as anti-depressants, opioid painkillers, antihistamines, corticosteroids, H2 blockers, hypnotics and many others. Xerostomia has been reported to be the fourth commonest side-effect of chemotherapy and the third most distressing (Zanni, Pharmacy Times August, 2007). In one study of breast cancer patients undergoing adjuvant chemotherapy, 44% were found to have significant hypofunction of salivary glands and 39% complained of xerostomia one year after chemotherapy (Jensen et al., 2008, Oral Oncology 44:162-173). In bone marrow transplant patients, impairment of salivary gland function, with a dramatic reduction in salivary flow has been seen one month after transplant, with only partial recovery after 4 months (Jacobson et al. 1996, Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 81:38-43). By damaging salivary gland cells, chemotherapeutic agents may affect both the volume of saliva produced and its composition.
In advanced cancer patients, i.e. those with cancer considered to be incurable, palliative chemotherapy is often used to improve quality and duration of life. In addition to any xerostomia caused by such chemotherapy, such patients may well have to contend with the effects of advancing age, which can on its own contribute to a reduction of up to 40% in salivary flow, as well as multiple other xerostomic medications. In one study of 120 advanced cancer patients, 117 were receiving other medications known to cause xerostomia, with the median number of such drugs being 4 per patient (Davies et al. 2002, Oral Oncology, 38:680-685). In that series, 82% had abnormally low unstimulated whole salivary flow rate and 78% reported xerostomia. Another published series of 99 consecutive advanced cancer patients reported an 88% rate of dry mouth (Oneschuk et al. 2000, Support Care Cancer 8:372-376).
The management of salivary gland hypofunction involves treatment of the cause, symptomatic treatment and treatment of the complications. Symptomatic treatment involves the use of saliva substitutes or saliva stimulants.
A number of pharmacological agents have been used as salivary stimulants, including yohimbine and nicotinamide. The most widely used are parasympathomimetic drugs, choline esters or anticholinesterase drugs. The most well known is pilocarpine which acts primarily on muscarinic receptors. Muscarinic agonists when administered systemically tend to produce side effects including sweating and cardiovascular changes.
Bethanechol chloride, also called carbamyl-methylcholine chloride, is a known drug which has been used clinically for many years. It is available in tablets and as an injection and is used as a stimulant of the smooth muscle of the gastrointestinal tract, and in particular the urinary bladder. It can also be of value in certain cases of postoperative abdominal distension and gastroparesis. It is administered orally, preferably on an empty stomach in order to minimise nausea and vomiting. For the treatment of acute post-operative or post-partum non-obstructive urinary retention or neurogenic atony of the bladder with retention, an oral dosage of 10-50 mg of bethanechol chloride 3-4 times daily is recommended.
It has been reported that bethanechol chloride given at 25 mg four times a day can cause significant side-effects, such as abdominal cramping, blurred vision, fatigue and an increase in urinary frequency. The drug has also been administered by subcutaneous injection, however, parenteral dosage forms are no longer available in the USA. It has been reported that a severe cholinergic reaction is likely to occur if it is given by the i.v. or i.m. routes. Severe reactions have also been reported after subcutaneous injection. Bethanechol is contraindicated in patients with hyperthyroidism, peptic ulcer, latent or active bronchial asthma, coronary artery disease, mechanical obstruction of the GI tract or bladder neck, marked vagotonia, epilepsy, parkinsonism, spastic GI disturbances, peritonitis or acute inflammatory conditions of the GI tract, pronounced bradycardia or hypotension or vasomotor instability. The safety and efficacy of bethanechol in paediatric patients have not been established.
Bethanechol administered orally has been tested in the treatment of xerostomia in a small number of clinical studies. The drug has been reported to increase salivary flow. Available data suggest that effects on salivation are dose-related, up to the maximum dose which may be safely administered via the oral route. In one study in patients with head and neck cancer-associated xerostomia, it was reported that of a total of 55 patients who were considered for enrolment, 12 (22%) were not eligible to take oral bethanechol due to systemic conditions (Jham et al. 2007, Oral Oncol. 43:137-142).
One potential way to increase efficacy and yet avoid further side-effects could be to give drugs by topical application to the oral mucosa in order to directly target the underlying minor salivary glands. For this to work the drug must be able to cross the oral mucosal membrane. The concept of buccal drug delivery is well known and a number of reviews on the subject have been published; see for example Buccal Drug Delivery by John Smart (2005), Expert Opin. Drug Deliv., 2(3):507-517. In the abstract of this article, it concludes that “The buccal mucosa, however, while avoiding first pass effects is a formidable barrier to drug absorption”. And later “Currently this route is restricted to the delivery of a limited number of small lipophilic molecules that readily cross the buccal mucosa”. In general, drug permeability across buccal tissue is dependent upon physiochemical properties of the drug, such as lipophilicity, molecular weight, and degree of ionisation at physiological pH. There are two possible routes of absorption through the squamous stratified epithelium of the oral mucosa, these being transcellular (intracellular, passing through the cell) and paracellular (intercellular, passing around the cell). Permeation has been reported to be mainly by the paracellular route through the intracellular lipids produced by membrane-coating granules; however, the route taken depends upon the physicochemical properties of the drug. Generally small molecules that are predominantly lipophilic, with a Log P range of 1.6-3.3, are absorbed most rapidly, and most drugs delivered successfully via the buccal or sublingual route are lipophilic. A compound with a Log P value of less than 0 or less than 1 is usually considered too hydrophilic to be a drug candidate, particularly if it needs to cross lipophilic biological membranes for its activity.
Chemically, bethanechol chloride is a quaternary ammonium compound, it is very polar in nature and has a high aqueous solubility (hydrophilic) and a calculated log P value of around −4.0. This is one of the lowest values reported in the literature for a clinically used pharmaceutical agent. Consistent with these physicochemical properties, bethanechol does not significantly penetrate into the CNS at therapeutic doses and is only poorly absorbed from the GI tract.